Cardiac muscle and skeletal muscle differ, however, in the level of intracellular [Ca++] attained after an action potential and hence in the number of actin-myosin interactions. In skeletal muscle, intracellular [Ca++] rises and the number of actin-myosin interactions is high after an action potential. In cardiac muscle, the rise in intracellular [Ca++] can be regulated, which affords the heart an important means of modulating the force of contraction without recruiting more muscle cells or undergoing tetany. Recall that in the heart, all the muscle cells are activated during a contraction, and so recruiting more muscle cells is not an option. Moreover, tetany of cardiac muscle cells would prevent any pumping action and thus be fatal. Consequently, the heart relies on different means of increasing the force of contraction, including varying the amplitude of the intracellular Ca++ transient.
Relaxation of Cardiac Muscle
Relaxation of skeletal muscle simply requires reaccumulation of Ca++ by the SR through the action of the sarcoplasmic endoplasmic reticulum calcium-ATPase (SERCA), also known as the SR Ca++ pump. Although SERCA plays a key role in the decrease in cytosolic [Ca++] in cardiac muscle, the process is more complex than that in skeletal muscle because some trigger Ca++ enters the cardiac muscle cell through the sarcolemmal calcium channels during each action potential. A mechanism must therefore exist to extrude this trigger Ca++; otherwise, the amount of Ca++ in the SR would continuously increase, and Ca++ overload would result. In particular, some Ca++ is extruded from the cardiac muscle cell though the sarcolemmal 3Na+-Ca++ antiporter and a sarcolemmal Ca++ pump (Fig. 13.2 ). The extracellular [Ca++] is in the millimolar range, whereas the amount of intracellular [Ca++] is submicromolar, and so extrusion of Ca++ is accomplished against a large chemical gradient. Similarly, [Na+] is considerably higher in the extracellular media than within the cell. The antiporter uses the Na+ gradient across the cell to power the uphill movement of Ca++ out of the cell. Because three Na+ ions enter the cell in exchange for one Ca++ ion, the 3Na+-Ca++ antiporter is electrogenic and creates a depolarizing current. The sarcolemmal Ca++ pump, on the other hand, uses the energy in ATP to extrude Ca++ from the cell. Both extrusion mechanisms and SERCA thus contribute to the relaxation of cardiac muscle by decreasing cytosolic [Ca++].
Although the interaction of actin and myosin requires a relatively small increase in free intracellular [Ca++], the abundance of Ca++-binding proteins in the myoplasm necessitates a much larger increase in total intracellular [Ca++]. The resting intracellular [Ca++] is approximately 50 to 100 nmol/L; half-maximal force of contraction requires approximately 600 nmol/L of free Ca++ . However, because of Ca++-binding proteins such as parvalbumin and troponin C, the total myoplasmic concentration must increase by 70 µmol/L. As already noted, much of this increase in total myoplasmic [Ca++] occurs through release of Ca++ from the SR. In a number of species, including rabbits, dogs, cats, guinea pigs, and humans, uptake and release of Ca++ by the SR account for approximately 70% of the intracellular Ca++ transient. Thus up to 30% of the rise in intracellular [Ca++] may be attributable to influx of Ca++ through voltage-gated calcium channels in the sarcolemma, and the 3Na+-Ca++ antiporter contributes significantly to Ca++ extrusion during relaxation.
The sarcolemmal Ca++ pump is in lower abundance than the 3Na+-Ca++ antiporter but has a higher affinity for Ca++ and thus may contribute more to the regulation of resting intracellular [Ca++] (see